Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phospholipid-sensitive, Ca++-dependent protein kinase activity was investigated in the cytosol of melanoma cells. A protein kinase system was partially purified, and enzyme activity was found to be modulated by palmitoyl-carnitine. In order to link the actions of palmitoyl-carnitine on phospholipid-sensitive protein kinase activity and the already reported role of protein kinase C in cell division, we studied the action of palmitoyl-carnitine on melanoma cell growth by measuring colony forming ability in a soft agar culture system. Palmitoyl-carnitine was found to inhibit cell growth in a dose-dependent manner. These findings suggest that palmitoyl-carnitine (or long-chain acylcarnitine), a naturally occurring metabolite, may play a key role in the onset of cell division. We suggest that the action of palmitoyl-carnitine on phospholipid-dependent protein kinase activity is in part related to the molecular events linking protein kinase C activity and the ionic events in the initiation of cell growth.
Br J Dermatol 1988 Aug
PMID:Modulation by palmitoyl-carnitine of calcium activated, phospholipid-dependent protein kinase activity and inhibition of melanoma cell growth. 316 38

Tumor promoting phorbol esters, such as 12-0-tetradecanoylphorbol-13-acetate (TPA), when applied topically to mouse skin cause inflammation and hyperplasia. The major cellular phorbol ester receptor is a calcium and phospholipid dependent protein kinase, protein kinase C (PK-C). PK-C is directly activated by TPA and most of the responses of cells to TPA appear to be mediated by PK-C. This suggests that PK-C may play a key role as a mediator of inflammation and growth in TPA treated mouse skin. Sphingosine has been reported to be a potent inhibitor of PK-C in vitro and in intact leukocytes. We therefore have investigated the effects of sphingosine upon TPA-induced inflammation, hyperplasia, induction of ornithine decarboxylase (ODC) activity and ODC mRNA, and activation of PK-C in mouse skin. The results demonstrate that sphingosine is a potent inhibitor of all of the TPA-induced responses examined. These data are compatible with the hypothesis that PK-C is a major mediator of the phorbol ester response in mouse skin. Furthermore, PK-C inhibitors may have therapeutic potential in inflammatory skin diseases such as psoriasis.
J Invest Dermatol 1988 Nov
PMID:Sphingosine inhibits phorbol ester-induced inflammation, ornithine decarboxylase activity, and activation of protein kinase C in mouse skin. 317 Dec 22

Tumor-promoting phorbol esters such as 12-0-tetradecanoylphorbol-13-acetate (TPA) cause epidermal inflammation and hyperplasia similar to that observed in psoriasis. Recent evidence suggests that these effects are mediated by a calcium/phospholipid-dependent protein kinase (protein kinase C), which is quantitatively the major cellular phorbol ester receptor. This report describes the partial purification and biochemical properties of this enzyme from adult human epidermis. Protein kinase C activity was purified 30-fold from high speed supernatants prepared from homogenates of keratome biopsies obtained from healthy volunteers. The partially purified preparation had a specific activity of 1.2 nmol/min/mg protein and an apparent molecular weight of 79,400. Activity was dependent on the presence of calcium and phosphatidylserine. At low calcium concentration (less than 0.1 mM) activity was greatly stimulated by 1,2-dioleoylglycerol. TPA mimicked the effect of diglyceride on enzyme activity, and the partially purified enzyme specifically bound phorbol dibutyrate (Kd = 2 nM). Protein kinase C activity was also present in the membrane fraction from adult human epidermis, and possessed properties similar to those of the cytosolic enzyme. We conclude that protein kinase C is present in human epidermis and is activated by TPA in a manner similar to that described for this enzyme from other tissues. These data lay the foundation for studying the role of protein kinase C in the regulation of epidermal growth and maturation.
J Invest Dermatol 1987 Nov
PMID:Purification and characterization of calcium/phospholipid-dependent kinase from adult human epidermis. 347 19

The application of hexadecane on animals skin induces hyperkeratinization and hyperplasia of the epidermis, however, the initial mechanisms of the epidermal cell proliferation and keratinization by hexadecane stimulation remains unknown. Protein kinase C is reported to be one of the critical enzymes involved in proliferation and differentiation of various cells and tissues. Therefore we investigated the effects of hexadecane on protein kinase C in pig epidermis. Protein kinase C activity of the pig skin increased 10 min after topical application of hexadecane to the back of the pig, normalized at 30 min, and subsequently kept falling for 24 h. In studying hexadecane dropped on floating sliced pig skin in Krebs buffer, similar results were obtained for the short term. Immediately after the hexadecane treatment, protein kinase C activity was not altered as compared with that of the untreated skin. Thus, the alteration of the protein kinase C activity after the hexadecane treatment is not due to the direct effect of hexadecane on the enzyme, but is due to other as yet unknown mechanisms of epidermal cell kinetics in response to hexadecane stimulation. We discuss the mechanisms of protein kinase C activity alteration upon treatment with hexadecane.
Arch Dermatol Res 1987
PMID:Effect of hexadecane on protein kinase C of pig epidermis. 367 64

Dithranol (0.01-1 micrograms/ml), but not the auto-oxidized form, caused a dose-related enhancement of the generation of reactive oxidants by leukoattractant-activated polymorphonuclear leukocytes (PMNL) in vitro. At the same concentrations dithranol inhibited both PMNL migration to leukoattractants and mitogen-stimulated mononuclear leukocyte (MNL) proliferation. Catalase (50-100 units/ml) protected both PMNL migration and MNL proliferation from dithranol whilst ascorbate and cysteine (1 mM), which maintain dithranol in the biologically active reduced state, potentiated the inhibition. To establish the molecular mechanism of the pro-oxidative activity of dithranol its effects on cytosolic protein kinase C (PKC) activity were investigated. Dithranol caused a dose-related activation of PKC by apparent substitution for 1,2-diolein. These results demonstrate that dithranol, but not its auto-oxidation products, activates PKC which in turn initiates the generation of reactive oxidants by PMNL. Since reactive oxidants are immunosuppressive the therapeutic mechanisms of dithranol may be related to pro-oxidative interactions of this agent with skin phagocytes.
Br J Dermatol 1987 Oct
PMID:Dithranol mediates pro-oxidative inhibition of polymorphonuclear leukocyte migration and lymphocyte proliferation. 367 90

To study the possible involvement of protein kinase C in psoriasis, we determined the activity of this enzyme in involved and uninvolved epidermis from psoriasis patients as well as in normal epidermis from controls. Protein kinase C activity was measured in the 100,000 g supernatants and in the detergent-solubilized particulate fractions of tissue homogenates after partial purification by DEAE-cellulose chromatography. The total enzyme activities per gram protein for normal, involved, and uninvolved epidermis were 127 +/- 11.9 mU/g, 64.7 +/- 8.6 mU/g, and 88.5 +/- 14.4 mU/g, respectively. The respective values for total enzyme activity per mg DNA were 7.04 +/- 0.48 mU/mg, 4.28 +/- 0.54 mU/mg, and 5.02 +/- 0.66 mU/mg. By both data bases, protein kinase C activity was statistically lower in the psoriatic skin biopsies than in those from control persons, whereas no significant difference was found between involved and uninvolved epidermis from psoriasis patients. We hypothesize that alterations in protein kinase C-mediated processes due to decreased protein kinase C activity may play a significant role in the pathophysiology of psoriasis.
J Invest Dermatol 1987 Feb
PMID:Decreased protein kinase C activity in psoriatic versus normal epidermis. 380 58

12-o-Tetradecanoylphorbol-13-acetate (TPA) activates calcium-activated, phospholipid-dependent protein kinase (protein kinase C) partially purified in an ion exchange column from pig epidermis. Protein kinase C was activated by TPA in a concentration-dependent manner with simultaneous addition of Ca2+ and phospholipid. Polyprenoic acid derivative (E5166) which is a newly synthesized retinoic acid derivative, inhibited the TPA activation of protein kinase C. This inhibition may explain the mechanisms by which retinoids inhibit TPA-induced tumor promotion.
Arch Dermatol Res 1986
PMID:Effects of 12-o-tetradecanoylphorbol-13-acetate and polyprenoic acid derivative on calcium-activated phospholipid-dependent protein kinase of pig skin. 381 53

Fas antigen is a cell membrane protein that has been suggested to mediate apoptosis. Using SV40-transformed human keratinocytes, we investigated the Fas-antigen-dependent apoptotic process. The expression of Fas antigen mRNA was markedly induced by interferon-gamma (IFN-gamma) treatment (500 U/ml). After IFN-gamma treatment in the presence of anti-Fas monoclonal antibody, apoptosis was induced, as detected by the formation of nucleosome-sized fragments of DNA and morphologically by apoptotic cells with round homogeneous nuclear beads detected by acridine orange staining. The apoptotic SV40-transformed keratinocytes were analyzed quantitatively by enzyme-linked immunosorbent assay using antihistone and peroxidase-conjugated anti-DNA antibodies to detect cell death. The IFN-gamma- and anti-Fas antibody-dependent apoptotis was observed by 3 h, and the maximal response was observed by 12 h. The induction of apoptosis was significantly augmented by treatment with 10 ng/ml 12-o-tetradecanoyl-phorbol-13-acetate (TPA). TPA alone had no effect on either Fas antigen expression or on the apoptotic process. Other protein kinase C activators (1-oleoyl-2-acetylglycerol and mezerein) also stimulated IFN-gamma-dependent apoptosis, whereas 4-o-methyl phorbol myristate acetate, a very weak protein kinase C activator, had only a slight effect. The TPA-induced augmentation of apoptosis was inhibited by the protein kinase C inhibitor, 1-(5-isoquinoline-sulfonyl)-2-methyl piperazine dihydrochloride (H-7). However, H-7 inhibited only the TPA-induced augmentation of apoptosis; the basal IFN-gamma- and anti-Fas-dependent apoptosis remained in the presence of H-7. Northern blot analysis revealed that c-jun mRNA was induced by IFN-gamma plus anti-Fas antibody treatment as well as by TPA treatment; the addition of IFN-gamma alone to the incubation medium had no effect on the expression of c-jun mRNA. These results indicate that IFN-gamma induces a Fas-antigen-dependent apoptotic process in SV40-transformed keratinocytes and that TPA augments the process through the activation of protein kinase C.
J Invest Dermatol 1995 Dec
PMID:Interferon-gamma-dependent stimulation of Fas antigen in SV40-transformed human keratinocytes: modulation of the apoptotic process by protein kinase C. 749 Apr 76

Protein tyrosine kinases (PTKs) are closely related to cell growth, proliferation and differentiation. In keratinocytes, various growth factor receptors and cytosolic proteins, including the EGF and IGF receptors, the proteins of the src family and others, exhibit PTK activity. In psoriatic epidermis an increased level of EGF receptors and their ligand TGF-alpha has been found, and this is thought to be one reason for the pathological hyperproliferation of keratinocytes in this disease. Oral treatment with cyclosporin A (CsA) and FK506 or topical treatment with dithranol lead to an improvement in psoriasis. In the present study we examined the effect of these three drugs on the cellular content of phosphorylated tyrosines in highly proliferative HaCaT keratinocytes. HaCaT keratinocytes can be used as a model for highly proliferative epidermis, e.g. psoriatic epidermis. CsA had no effect whereas FK506 and dithranol reduced the phosphorylation of tyrosine residues in HaCaT keratinocytes. The activation of serine/threonine protein kinase C (PKC) is known to downregulate PTKs. Therefore we incubated keratinocytes with the selective PKC inhibitor Ro 31-8220 in addition to the other drugs. Only after the addition of Ro 31-8220 to FK506-treated keratinocytes was the phosphotyrosine (p-tyr) level elevated, but this was only one-third of the increase measured without additional therapeutic drugs. We assume that an induction of PKC alone is not responsible for the reduced p-tyr level after treatment with dithranol and FK506.(ABSTRACT TRUNCATED AT 250 WORDS)
Arch Dermatol Res 1995
PMID:Cyclosporin A, FK506 and dithranol after tyrosine-specific protein phosphorylation in HaCaT keratinocytes. 754 Nov 91

The family of protein kinase C (PKC) isoenzymes plays a fundamental part in signal transduction, and thereby regulates important cellular functions, including growth, differentiation, cytokine production and adhesion molecule expression. In lesional psoriatic skin, Ca(2+)-dependent PKC activity, PKC-beta protein and epidermal Langerhans cell (LC) PKC-beta immunostaining are significantly decreased, indicating activation and subsequent down-regulation of PKC. Whether these changes occur in other inflammatory/hyperplastic dermatoses is, however, unknown. We examined PKC-alpha and PKC-beta expression in normal skin, psoriasis, cutaneous T-cell lymphoma (CTCL), lamellar ichthyosis, non-bullous ichthyosiform erythroderma, atopic dermatitis, urushiol-induced allergic contact dermatitis, and sodium lauryl sulphate (SLS)-induced irritant contact dermatitis. Cryostat sections were stained for PKC-alpha and PKC-beta, and the LC marker CD1a, using an immunoperoxidase technique and specific monoclonal antibodies. Double-labelling studies, in normal skin, revealed co-expression of PKC-beta and CD1a by epidermal LCs. Analysis of the number of PKC-beta+ and CD1a+ epidermal LCs, in diseased compared with normal skin, revealed three categories: (i) in psoriasis and CTCL, the PKC-beta+ epidermal LC number was significantly reduced, whereas the CD1a+ epidermal LC number was unchanged; (ii) in allergic and irritant contact dermatitis, both PKC-beta+ and CD1a+ epidermal LCs were significantly reduced in number; and (iii) in atopic dermatitis, the PKC-beta+ epidermal LC number was normal, and CD1a+ epidermal LCs were significantly increased in number. Moreover, the ratio of epidermal LC PKC+/CD1a+ was reduced in all the dermatoses studied, suggesting activation of PKC-beta, with subsequent down-regulation. Within the dermis, increased PKC-beta staining of infiltrating cells was observed in all the conditions studied except lamellar ichthyosis and non-bullous ichthyosiform erythroderma. These data indicate that: (i) down-regulation of LC PKC-beta occurs in a variety of inflammatory and hyperplastic skin disorders, and is not unique to psoriasis, and (ii) the pattern of epidermal LC PKC-beta and CD1a expression varies among the diseases studied. In mice, PKC activation induces LC migration. Thus, down-regulation of epidermal LC PKC-beta associated with reduced CD1a+ epidermal LCs in allergic and irritant contact dermatitis suggests that PKC-beta may transduce the signal for migration of LCs from human epidermis.
Br J Dermatol 1995 Aug
PMID:Down-regulation of Langerhans cell protein kinase C-beta isoenzyme expression in inflammatory and hyperplastic dermatoses. 754 80


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